tbuckley/cabot-search huggingface dataset:
Combining different CRISPR nucleases for simultaneous knock-in and base editing prevents translocations in multiplex-edited CAR T cells
Authors: Viktor Glaser, Christian Flugel, Jonas Kath, Weijie Du, Vanessa Drosdek, Clemens Franke, Maik Stein, Axel Pruß, Michael Schmueck-Henneresse, Hans-Dieter Volk, Petra Reinke, Dimitrios L. Wagner
Journal: Genome biology (2023)

Multiple genetic modifications may be required to develop potent off-the-shelf chimeric antigen receptor (CAR) T cell therapies. Conventional CRISPR-Cas nucleases install sequence-specific DNA double-strand breaks (DSBs), enabling gene knock-out or targeted transgene knock-in. However, simultaneous DSBs provoke a high rate of genomic rearrangements which may impede the safety of the edited cells.
A graph neural network-based interpretable framework reveals a novel DNA fragility–associated chromatin structural unit
Authors: Yu Sun, Xiang Xu, Lin Lin, Kang Xu, Yang Zheng, Chao Ren, Huan Tao, Xu Wang, Huan Zhao, Weiwei Tu, Xuemei Bai, Junting Wang, Qiya Huang, Yaru Li, Hebing Chen, Hao Li, Xiaochen Bo
Journal: Genome biology (2023)

Abstract Background DNA double-strand breaks (DSBs) are among the most deleterious DNA lesions, and they can cause cancer if improperly repaired. Recent chromosome conformation capture techniques, such as Hi-C, have enabled the identification of relationships between the 3D chromatin structure and DSBs, but little is known about how to explain these relationships, especially from global contact maps, or their contributions to DSB formation. Results Here, we propose a framework that integrates graph neural network (GNN) to unravel the relationship between 3D chromatin structure and DSBs using an advanced interpretable technique GNNExplainer. We identify a new chromatin structural unit named the DNA fragility–associated chromatin interaction network (FaCIN). FaCIN is a bottleneck-like structure, and it helps to reveal a universal form of how the fragility of a piece of DNA might be affected by the whole genome through chromatin interactions. Moreover, we demonstrate that neck interactions in FaCIN can serve as chromatin structural determinants of DSB formation. Conclusions Our study provides a more systematic and refined view enabling a better understanding of the mechanisms of DSB formation under the context of the 3D genome.
Which one is better for refractory/relapsed acute B-cell lymphoblastic leukemia: Single-target (CD19) or dual-target (tandem or sequential CD19/CD22) CAR T-cell therapy?
Authors: Sining Liu, Xinyue Zhang, Haiping Dai, Wei Cui, Jia Yin, Zheng Li, Xiao Yang, Chunxiu Yang, Shengli Xue, Huiying Qiu, Miao Miao, Suning Chen, Zhengming Jin, Chengcheng Fu, Caixia Li, Aining Sun, Yue Han, Ying Wang, Lei Yu, Depei Wu, Qingya Cui, Xiaowen Tang
Journal: Blood Cancer Journal (2023)

Abstract CD19 chimeric antigen receptor (CAR) T-cell therapy has shown great success against B-cell acute lymphoblastic leukemia (B-ALL). Tandem and sequential CD19/CD22 dual-target CAR T-cell therapies have been developed to reduce the possibility of CD19-negative relapse; however, the superior strategy is still uncertain. This study screened 219 patients with relapsed/refractory B-ALL who were enrolled in clinical trials of either CD19 (NCT03919240) or CD19/CD22 CAR T-cell therapy (NCT03614858). The complete remission (CR) rates in the single CD19, tandem CD19/CD22, and sequential CD19/CD22 groups were 83.0% (122/147), 98.0% (50/51), and 95.2% (20/21), respectively (single CD19 vs. tandem CD19/CD22, P = 0.006). Patients with high-risk factors achieved a higher rate of CR in the tandem CD19/CD22 group than in the single CD19 group (100.0% vs. 82.4%, P = 0.017). Tandem CD19/CD22 CAR T-cell therapy was one of the significant favorable factors in the multivariate analysis of the CR rate. The incidence of adverse events was similar among the three groups. Multivariable analysis in CR patients showed that a low frequency of relapse, a low tumor burden, minimal residual disease-negative CR and bridging to transplantation were independently associated with better leukemia-free survival. Our findings suggested that tandem CD19/CD22 CAR T-cell therapy obtains a better response than CD19 CAR T-cell therapy and a similar response to sequential CD19/CD22 CAR T-cell therapy.
Transformation of alignment files improves performance of variant callers for long-read RNA sequencing data
Authors: Vladimir B. C. de Souza, Ben T. Jordan, Elizabeth Tseng, Elizabeth A. Nelson, Karen K. Hirschi, Gloria Sheynkman, Mark D. Robinson
Journal: Genome biology (2023)

Long-read RNA sequencing (lrRNA-seq) produces detailed information about full-length transcripts, including novel and sample-specific isoforms. Furthermore, there is an opportunity to call variants directly from lrRNA-seq data. However, most state-of-the-art variant callers have been developed for genomic DNA. Here, there are two objectives: first, we perform a mini-benchmark on GATK, DeepVariant, Clair3, and NanoCaller primarily on PacBio Iso-Seq, data, but also on Nanopore and Illumina RNA-seq data; second, we propose a pipeline to process spliced-alignment files, making them suitable for variant calling with DNA-based callers. With such manipulations, high calling performance can be achieved using DeepVariant on Iso-seq data.
Correction to: The function and mechanisms of action of circular RNAs in Urologic Cancer
Authors: Zi-hao Zhang, Yue Wang, Ya Zhang, Sheng-Feng Zheng, Tao Feng, Xi Tian, Mierxiati Abudurexiti, Zhen-Da Wang, Wen-Kai Zhu, Jia-Qi Su, Hai-Liang Zhang, Guo-Hai Shi, Zi-Liang Wang, Da-Long Cao, Ding-Wei Ye
Journal: Molecular Cancer (2023)
A desert lncRNA HIDEN regulates human endoderm differentiation via interacting with IMP1 and stabilizing FZD5 mRNA
Authors: Pei Lu, Jie Yang, Mao Li, Shanshan Wen, Tianzhe Zhang, Chenchao Yan, Ran Liu, Yu Xiao, Xinghuan Wang, Wei Jiang
Journal: Genome biology (2023)

Extensive studies have revealed the function and mechanism of lncRNAs in development and differentiation, but the majority have focused on those lncRNAs adjacent to protein-coding genes. In contrast, lncRNAs located in gene deserts are rarely explored. Here, we utilize multiple differentiation systems to dissect the role of a desert lncRNA, HIDEN (human IMP1-associated "desert" definitive endoderm lncRNA), in definitive endoderm differentiation from human pluripotent stem cells.We show that desert lncRNAs are highly expressed with cell-stage-specific patterns and conserved subcellular localization during stem cell differentiation. We then focus on the desert lncRNA HIDEN which is upregulated and plays a vital role during human endoderm differentiation. We find depletion of HIDEN by either shRNA or promoter deletion significantly impairs human endoderm differentiation. HIDEN functionally interacts with RNA-binding protein IMP1 (IGF2BP1), which is also required for endoderm differentiation. Loss of HIDEN or IMP1 results in reduced WNT activity, and WNT agonist rescues endoderm differentiation deficiency caused by the depletion of HIDEN or IMP1. Moreover, HIDEN depletion reduces the interaction between IMP1 protein and FZD5 mRNA and causes the destabilization of FZD5 mRNA, which is a WNT receptor and necessary for definitive endoderm differentiation.These data suggest that desert lncRNA HIDEN facilitates the interaction between IMP1 and FZD5 mRNA, stabilizing FZD5 mRNA which activates WNT signaling and promotes human definitive endoderm differentiation.
CancerGPT for few shot drug pair synergy prediction using large pretrained language models
Authors: Tianhao Li, Sandesh Shetty, Advaith Kamath, Ajay Jaiswal, Xiaoqian Jiang, Ying Ding, Yejin Kim
Journal: npj Digital Medicine (2024)

Large pre-trained language models (LLMs) have been shown to have significant potential in few-shot learning across various fields, even with minimal training data. However, their ability to generalize to unseen tasks in more complex fields, such as biology, has yet to be fully evaluated. LLMs can offer a promising alternative approach for biological inference, particularly in cases where structured data and sample size are limited, by extracting prior knowledge from text corpora. Our proposed few-shot learning approach uses LLMs to predict the synergy of drug pairs in rare tissues that lack structured data and features. Our experiments, which involved seven rare tissues from different cancer types, demonstrated that the LLM-based prediction model achieved significant accuracy with very few or zero samples. Our proposed model, the CancerGPT (with ~ 124M parameters), was even comparable to the larger fine-tuned GPT-3 model (with ~ 175B parameters). Our research is the first to tackle drug pair synergy prediction in rare tissues with limited data. We are also the first to utilize an LLM-based prediction model for biological reaction prediction tasks.
The Surveillance of Infectious Diseases
Authors: Stephen B. Thacker
Journal: JAMA (1983)

Surveillance is the collection, collation, and analysis of data and the dissemination to those who need to know so that an action can result. This article describes the clinician's critical role in disease reporting and outlines the benefits of surveillance to clinical practice. Four commonly used systems of disease surveillance are notifiable disease reporting, laboratory-based surveillance, hospital-based surveillance, and population-based surveillance. We analyze the relative strengths and limitations of each of these systems and present current efforts to evaluate and improve surveillance activities. (<i>JAMA</i>1983;249:1181-1185)
Increased expression of intercellular adhesion molecule 1 on bile ducts in primary biliary cirrhosis and primary sclerosing cholangitis
Authors: David H. Adams, Stefan G. Hubscher, Jean Shaw, Gerald D. Johnson, Christopher Babbs, Robert Rothlein, James M. Neuberger
Journal: Hepatology (1991)

It has been suggested that immunological mechanisms involving lymphocyte-mediated damage are important in the characteristic bile-duct damage that occurs in primary biliary cirrhosis and primary sclerosing cholangitis. Because adhesion is necessary for the interaction of lymphocytes with their target structures, we have studied the expression of intercellular adhesion molecule 1, a ligand for the leukocyte adhesion receptor lymphocyte function—associated antigen 1 in the liver of patients with primary biiary cirrhosis and primary sclerosing cholangitis. Strong expression of intercellular adhesion molecule 1 was seen on interlobular bile ducts and proliferating bile ductules in both conditions. In primary biliary cirrhosis, medium-sized ducts, which are spared by the disease, were negative. Minimal bile-duct staining was seen in conditions in which bile-duct damage is not a major feature, such as nonbiliary cirrhosis and acute liver diseases. In patients with cirrhosis from any cause, strong expression of intercellular adhesion molecule 1 was detected on the periseptal hepatocytes adjacent to new connective tissue. The intensity of immunohistochemical staining was recorded using a semiquantitative visual scoring system that was subsequently validated quantitatively by confocal laser scanning microscopy. The expression/induction of intercellular adhesion molecule 1 on bile ducts may be important in the pathogenesis of bile-duct damage in primary biliary cirrhosis and primary sclerosing cholangitis and is further evidence to support an immune pathogenesis in these two conditions. Furthermore, the induction of intercellular adhesion molecule 1 on hepatocytes may be an important factor in the liver-cell damage and fibrosis that occur during the development of cirrhosis.
Continuous Varicella-Zoster Infection Associated With Acyclovir Resistance in a Child With AIDS
Authors: Savita Pahwa
Journal: JAMA (1988)

Acyclovir has become the treatment of choice for varicella-zoster virus (VZV) infections in immunocompromised individuals. This article describes a 4-year-old girl congenitally infected with human immunodeficiency virus who developed a continuous cutaneous infection with VZV that persisted over a 14-month period until her death. Initial episodes of varicella and zoster were responsive to acyclovir treatment; however, subsequent recurrences necessitated administration of multiple courses of acyclovir. Lesions became markedly hyperkeratotic, slow healing, and persistent despite acyclovir therapy. Numerous attempts to isolate virus from the lesions yielded only one isolate late in the course of therapy. This virus clearly demonstrated acyclovir resistance in vitro. Bizarre manifestations of VZV infection could present both diagnostic and therapeutic dilemmas. Prolonged acyclovir treatment of highly immunocompromised patients with acquired immunodeficiency syndrome and severe VZV may lead to the appearance of resistant virus. (<i>JAMA</i>1988;260:2879-2882)
Risk of Febrile Seizures and Epilepsy After Vaccination With Diphtheria, Tetanus, Acellular Pertussis, Inactivated Poliovirus, and Haemophilus Influenzae Type b
Authors: Yuelian Sun, Jakob Christensen, Anders Hviid, Jiong Li, Peter Vedsted, Jørn Olsen, Mogens Vestergaard
Journal: JAMA (2012)
CONSORT Harms 2022 statement, explanation, and elaboration: updated guideline for the reporting of harms in randomised trials
Authors: Daniela R Junqueira, Liliane Zorzela, Susan Golder, Yoon Loke, Joel J Gagnier, Steven A Julious, Tianjing Li, Evan Mayo-Wilson, Ba Pham, Rachel Phillips, Pasqualina Santaguida, Roberta W Scherer, Peter C Gøtzsche, David Moher, John P A Ioannidis, Sunita Vohra
Journal: BMJ (2023)

Randomised controlled trials remain the reference standard for healthcare research on effects of interventions, and the need to report both benefits and harms is essential. The Consolidated Standards of Reporting Trials (the main CONSORT) statement includes one item on reporting harms (ie, all important harms or unintended effects in each group). In 2004, the CONSORT group developed the CONSORT Harms extension; however, it has not been consistently applied and needs to be updated. Here, we describe CONSORT Harms 2022, which replaces the CONSORT Harms 2004 checklist, and shows how CONSORT Harms 2022 items could be incorporated into the main CONSORT checklist. Thirteen items from the main CONSORT were modified to improve harms reporting. Three new items were added. In this article, we describe CONSORT Harms 2022 and how it was integrated into the main CONSORT checklist, and elaborate on each item relevant to complete reporting of harms in randomised controlled trials. Until future work from the CONSORT group produces an updated checklist, authors, journal reviewers, and editors of randomised controlled trials should use the integrated checklist presented in this paper.
Gain-of-function variants in the <i>KDF1</i> gene cause hidradenitis suppurativa associated with ectodermal dysplasia by stabilizing IκB kinase α
Authors: Alban Ziegler, Frédéric Ebstein, Hanan Shamseldin, Clément Prouteau, Elke Krüger, Yousef M Binamer, Dominique Bonneau, Fowzan S Alkuraya, Ludovic Martin
Journal: British Journal of Dermatology (2023)

Keratinocyte differentiation factor (KDF)1 has been shown to cause ectodermal dysplasia with or without hidradenitis suppurativa in a single family. KDF1 is known to regulate epidermal differentiation through its interaction with IκB kinase (IKK)α. We report a novel de novo KDF1 variant (p.His254Tyr) in a 20-year-old male patient presenting with hidradenitis suppurativa and ectodermal dysplasia. We demonstrate that variants in KDF1 associated with hidradenitis suppurativa actually cause pathogenic gain-of-function of KDF1 through upregulation of IKKα. Ectodermal dysplasia may be present in a subset of individuals with hidradenitis suppurativa and should be investigated. Inhibition of IKKα appears to be a suitable therapeutic target for these individuals.
Colorectal cancer and advanced adenoma incidence during post-polypectomy surveillance: a national cohort study in the English Bowel Cancer Screening Programme
Authors: Linda Sharp, Matthew D. Rutter, Stewart N. Bonnington, A. Pali S. Hungin, Claire Nickerson, Suzanne Wright
Journal: Endoscopy (2023)

Improved colonoscopy quality has led to debate about whether all post-polypectomy surveillance is justified. We evaluated surveillance within the English Bowel Cancer Screening Programme (BCSP) to determine the yield of surveillance and identify predictive factors for surveillance outcome.We performed a retrospective cohort study of individuals undergoing post-polypectomy surveillance between July 2006 and January 2017. BCSP records were linked to the National Cancer Registration Database to identify interval-type post-colonoscopy colorectal cancers (CRCs). Advanced adenoma and CRC at surveillance were documented. CRC incidence was compared with the general population using standardized incidence ratios (SIRs). Predictors of advanced adenomas at first surveillance (S1), and CRC during follow-up, were identified.44 151 individuals (23 078 intermediate risk; 21 073 high risk) underwent 64 544 surveillance episodes. Advanced adenoma and CRC yields were, respectively, 10.0 % and 0.5 % at S1, 8.5 % and 0.4 % at S2, and 10.8 % and 0.4 % at S3. S1 yield was lowest in those with one index adenoma ≥ 10 mm (advanced adenoma 6.1 %; CRC 0.3 %). The SIR was 0.76 (95 %CI 0.66-0.88), accounted for by the intermediate risk group (intermediate risk SIR 0.61, 95 %CI 0.49-0.75; high risk SIR 0.95, 95 %CI 0.79-1.15). Adenoma multiplicity, presence of a large nonpedunculated adenoma, and greater villous component were associated with advanced adenoma at S1. Older age and multiplicity were significantly associated with CRC risk.This large, national analysis found low levels of CRC in those undergoing surveillance and low advanced adenoma yield in most subgroups. Less intensive surveillance in some subgroups is warranted, and surveillance may be avoided in those with a single large adenoma.
Transportation barriers, emergency room use, and mortality risk among US adults by cancer history
Authors: Changchuan Jiang, K Robin Yabroff, Lei Deng, Qian Wang, Stuthi Perimbeti, Charles L Shapiro, Xuesong Han
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Lack of safe, reliable, and affordable transportation is a barrier to medical care, but little is known about its association with clinical outcomes. Methods We identified 28 640 adults with and 470 024 adults without a cancer history from a nationally representative cohort (2000-2018 US National Health Interview Survey) and its linked mortality files with vital status through December 31, 2019. Transportation barriers were defined as delays in care because of lack of transportation. Multivariable logistic and Cox proportional hazards models estimated the associations of transportation barriers with emergency room (ER) use and mortality risk, respectively, adjusted for age, sex, race and ethnicity, education, health insurance, comorbidities, functional limitations, and region. Results Of the adults, 2.8% (n = 988) and 1.7% (n = 9685) with and without a cancer history, respectively, reported transportation barriers; 7324 and 40 793 deaths occurred in adults with and without cancer history, respectively. Adults with a cancer history and transportation barriers, as compared with adults without a cancer history or transportation barriers, had the highest likelihood of ER use (adjusted odds ratio [aOR] = 2.77, 95% confidence interval [CI] = 2.34 to 3.27) and all-cause mortality risk (adjusted hazard ratio [aHR] = 2.28, 95% CI = 1.94 to 2.68), followed by adults without a cancer history with transportation barriers (ER use aOR = 1.98, 95% CI =1.87 to 2.10; all-cause mortality aHR = 1.57, 95% CI = 1.46 to 1.70) and adults with a cancer history but without transportation barriers (ER use aOR = 1.39, 95% CI = 1.34 to 1.44; all-cause mortality aHR = 1.59, 95% CI = 1.54 to 1.65). Conclusion Delayed care because of lack of transportation was associated with increased ER use and mortality risk among adults with and without cancer history. Cancer survivors with transportation barriers had the highest risk.
Survival of Patients With Neuroblastoma After Assignment to Reduced Therapy Because of the 12- to 18-Month Change in Age Cutoff in Children's Oncology Group Risk Stratification
Authors: Hannah G. Bender, Meredith S. Irwin, Michael D. Hogarty, Robert Castleberry, John M. Maris, Pei-Chi Kao, Fan F. Zhang, Arlene Naranjo, Susan L. Cohn, Wendy B. London
Journal: Journal of Clinical Oncology (2023)

In 2006, Children's Oncology Group (COG) reclassified subgroups of toddlers diagnosed with neuroblastoma from high-risk to intermediate-risk, when the age cutoff for high-risk assignment was raised from 365 days (12 months) to 547 days (18 months). The primary aim of this retrospective study was to determine if excellent outcome was maintained after assigned reduction of therapy.
18F-FDG PET–Positive Large Pelvic Granuloma Mimicking Malignant Bladder Tumor
Authors: Ceylan Altintas Taslicay, Isa Cam, Aziz Hakki Civriz, Onder Kara, Hakan Demir
Journal: Clinical Nuclear Medicine (2023)

An 88-year-old man was admitted to our hospital with a recurrent lower urinary tract infection. He had a history of open prostatectomy for benign prostatic hyperplasia 15 years ago and smoking. A mass arising within a bladder diverticula was suspected on the left lateral wall of the bladder on ultrasonography. Although no mass was observed in the bladder lumen on the cystoscopy, abdominal CT detected a left-sided pelvic soft tissue mass. A hypermetabolic mass was detected on 18 F-FDG PET/CT performed because of suspicion of malignancy, and it was excised. Granuloma secondary to chronic vasitis was diagnosed histopathologically.
Dynamic weighted hypergraph convolutional network for brain functional connectome analysis
Authors: Junqi Wang, Hailong Li, Gang Qu, Kim M. Cecil, Jonathan R. Dillman, Nehal A. Parikh, Lili He
Journal: Medical Image Analysis (2023)

The hypergraph structure has been utilized to characterize the brain functional connectome (FC) by capturing the high order relationships among multiple brain regions of interest (ROIs) compared with a simple graph. Accordingly, hypergraph neural network (HGNN) models have emerged and provided efficient tools for hypergraph embedding learning. However, most existing HGNN models can only be applied to pre-constructed hypergraphs with a static structure during model training, which might not be a sufficient representation of the complex brain networks. In this study, we propose a dynamic weighted hypergraph convolutional network (dwHGCN) framework to consider a dynamic hypergraph with learnable hyperedge weights. Specifically, we generate hyperedges based on sparse representation and calculate the hyper similarity as node features. The hypergraph and node features are fed into a neural network model, where the hyperedge weights are updated adaptively during training. The dwHGCN facilitates the learning of brain FC features by assigning larger weights to hyperedges with higher discriminative power. The weighting strategy also improves the interpretability of the model by identifying the highly active interactions among ROIs shared by a common hyperedge. We validate the performance of the proposed model on two classification tasks with three paradigms functional magnetic resonance imaging (fMRI) data from Philadelphia Neurodevelopmental Cohort. Experimental results demonstrate the superiority of our proposed method over existing hypergraph neural networks. We believe our model can be applied to other applications in neuroimaging for its strength in representation learning and interpretation.
Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Harry P Erba, Pau Montesinos, Hee-Je Kim, Elżbieta Patkowska, Radovan Vrhovac, Pavel Žák, Po-Nan Wang, Tsvetomir Mitov, James Hanyok, Yasser Mostafa Kamel, Jaime E Connolly Rohrbach, Li Liu, Aziz Benzohra, Arnaud Lesegretain, Jorge Cortes, Alexander E Perl, Mikkael A Sekeres, Hervé Dombret, Sergio Amadori, Jianxiang Wang, Mark J Levis, Richard F Schlenk
Journal: The Lancet (2023)